Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes
Open accessAbstract
Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allows for the generation of three-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation had markedly increased myofibril ultrastructural organization, elevated conduction velocity and improved both electrophysiological and Ca(2+) handling properties compared to nonstimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.
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Moderate positive chronotropy and reduction of stroke work at high isoproterenol doses are characteristic of immature tissues exhibiting poorly developed calcium handling, suggesting maturation protocols may be required to obtain positive force-frequency relationships as observed in healthy adult human ventricular myocardium.
“The moderate positive chronotropy and reduction of stroke work observed at high isoproterenol doses are characteristic of immature tissues exhibiting poorly developed calcium handling properties8, suggesting that maturation protocols14,21,22,73 may be required to obtain positive force-frequency relationships, as observed in healthy adult human ventricular myocardium74.”
From A tissue-engineered scale model of the heart ventricle (2018) · cites this paper as [14]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredEHTs have been successfully explored for disease modelling and drug compound screening.
“EHTs demonstrate good predictive value for human (patho-)physiology (Sacchetto et al., 2020) and have been successfully explored for disease modelling and drug compound screening (Hansen et al., 2010;Nunes et al., 2013;Schwach et al., 2024).”
From A human engineered mini-heart platform for mimicking ventricular pump function (2025) · cites this paper as Nunes et al., 2013
The Introduction (page unavailable) describes stem-cell-derived cardiac tissues as an opportunity for modelling diseased hearts and screening therapeutic agents. The Results (“Stimulation improves Ca2+ handling properties,” page unavailable) report responses to several compounds in biowire cells. Neither passage establishes that the biowires were successfully used for disease modelling or drug-compound screening; the paper primarily tests their maturation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe sarcomeric organization of hvCOC resembled other human engineered cardiac tissue constructs and differed from random clusters.
“with sarcomeric arrangements similar to other human engineered cardiac tissue constructs [14,21–23] but distinct from random clusters.”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [23]
Conventional EHTs typically consist of a strip of cardiac tissue formed around straight elastomeric supports or wires.
“These in vitro models typically consist of a strip of cardiac tissue formed around straight elastomeric supports or wires (Goldfracht et al., 2019;Nunes et al., 2013), consequently lacking the cavity that is necessary for fluid pumping function.”
From A human engineered mini-heart platform for mimicking ventricular pump function (2025) · cites this paper as Nunes et al., 2013
The structure and function of iPSC-CMs can be matured using mechanical and electrical stimulation, prolonged culture periods, and co-culture in the presence of CFs or endothelial cells.
“The structure and function of iPSC-CMs can be matured using mechanical and electrical stimulation42,49, prolonged culture periods64,65, and also co-culture in the presence of CFs or endothelial cells66.”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [42]
Electrical stimulation is among the most important biophysical cues that induce cardiomyocyte growth and maturation.
“Electrical stimulation is among the most important biophysical cues that induce CM growth and maturation [173–175].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [173]
In Biowire, cardiomyocytes aligned toward the suture, improving intercellular organization compared with age-matched embryoid bodies.
“Since CMs were aligned toward the suture, the overall intercellular organization significantly improved compared to the age-matched embryoid bodies.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [246]
The authors' team developed Biowire by seeding cardiac cells encapsulated in hydrogel into a PDMS microwell, where the cell suspension self-organized around a suture template.
“we developed Biowire [246], by seeding cardiac cells encapsulated in a hydrogel into a PDMS microwell, where the cardiac cell suspension self-organized around a suture template situated in the middle of the microwell.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [246]
Electrical stimulation with increasing ramping frequency improved Biowire maturation in electrophysiological and calcium evaluations.
“the incorporation of electrical stimulation of increasing ramping frequency improved the maturation level of Biowire significantly in terms of both electrophysiological and calcium evaluations.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [246]
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- Authors
- Nunes, S. S., Miklas, J. W., Liu, J., Aschar-Sobbi, R., Xiao, Y., Zhang, B., Jiang, J., Massé, S., Gagliardi, M., Hsieh, A., Thavandiran, N., Laflamme, M. A., Nanthakumar, K., Gross, G. J., Backx, P. H., Keller, G., & Radisic, M.
- Affiliations
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Toronto General Hospital (CA)
- University Health Network (CA)
- University of Washington (US)
- Corresponding author
- Radisic, Milica
- ORCID
- Venue
- Nature Methods
- Published
- 2013-06-23
- Volume
- 10
- Issue
- 8
- Pages
- 781-787
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC4071061
- OpenAlex
- W2035312069
- Cited by
- 952
- References
- 46
- Citations by year
- 2026: 33 · 2025: 53 · 2024: 74 · 2023: 78 · 2022: 82 · 2021: 103 · 2020: 97 · 2019: 85 · 2018: 70 · 2017: 80 · 2016: 82 · 2015: 65 · 2014: 42 · 2013: 8
- FWCI
- 29.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01hl076485-16)
- Canadian Institutes of Health Research (MOP62954, 120196_1, 104296_1, 385981-10, 126027_1)
- National Heart, Lung, and Blood Institute (2R01 HL076485, R01HL117991, P01HL094374, T32HL007828)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- cardiomyocyte maturation, human pluripotent stem cells, electrical stimulation, myofibril ultrastructure, conduction velocity, calcium handling, electrophysiology, pacing rate
- MeSH terms
- Cell Differentiation, Electric Stimulation, Humans, Myocardium, Cell Culture Techniques, Tissue Engineering, Myocytes, Cardiac, Microscopy, Electron, Transmission, Electrophysiological Phenomena, Induced Pluripotent Stem Cells
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